(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide: (S18986-1) a positive modulator of AMPA receptors enhances (S)-AMPA-mediated [3H]noradrenaline release from rat hippocampal and frontal cortex slices

Lockhart, Brian P.; Iop, Fabrice; Closier, Matthieu; Lestage, Pierre

doi:10.1016/s0014-2999(00)00433-7

Cited by 31 publications

(25 citation statements)

References 34 publications

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“…Brain-derived neurotrophic factor, IGF, GDNF and PDGF were purchased from R&D Systems (Minneapolis, MN, USA), wortmannin and Akt inhibitor from Sigma-Aldrich (St. Louis, MO, USA), JC-1 and DCF-DA from Molecular Probes (Carlsbad, CA, USA), PD98059 from New England Biolabs (Ipswich, MA, USA) and blocking anti-BDNF antibody from Chemicon (Temecula, CA, USA). Positive AMPA receptor modulator S18986 was synthesized as previously described 39 . The concentrations of factors and reagents used were as follows: BDNF (50 ng/ml), IGF (100 ng/ml), GDNF (100 ng/ml), PDGF (100 ng/ml), positive AMPA receptor modulator S18986 (50 mM), blocking anti-BDNF antibody (10 mg/ml), PD98059 (30 mM), wortmannin (200 nM) and Akt inhibitor (30 mM).…”

Section: Discussionmentioning

confidence: 99%

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

et al. 2009

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Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators include benzamide compounds that allosterically modulate AMPA glutamate receptors. These small molecules that cross the blood-brain barrier have been shown to act as a neuroprotectant by increasing the levels of endogenous brain-derived neurotrophic factor (BDNF). Positive AMPA receptor modulators have also been shown to increase the levels of growth-associated protein-43 (GAP-43). GAP-43 plays a major role in many aspects of neuronal function in vertebrates. The goal of this study was to determine whether GAP-43 was important in mediating the actions of positive AMPA receptor modulator (S18986) and BDNF. Using cortical cultures from GAP-43 knockout and control mice, we show that (1) GAP-43 is upregulated in response to S18986 and BDNF in control cultures; (2) this upregulation of GAP-43 is essential for mediating the neuroprotective effects of S18986 and BDNF; (3) administration of S18986 and BDNF leads to an increase in the expression of the glutamate transporters GLT-1 and GLAST that are key to limiting excitotoxic cell death and this increase in GLT-1 and GLAST expression is completely blocked in the absence of GAP-43. Taken together this study concludes that GAP-43 is an important mediator of the neurotrophic effects of S18986 and BDNF on neuronal survival and plasticity, and is essential for the success of positive AMPA receptor modulator-BDNF-based neurotrophin therapy. Positive a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators allosterically modulate AMPA-type glutamate receptors and facilitate fast excitatory transmission, 1,2 and have been shown to enhance learning and memory. [3][4][5] Positive AMPA receptor modulators also decrease neuronal loss in excitotoxic neonatal brain lesions. 6 Thus, positive AMPA receptor modulators are potential candidates for treatment of diseases characterized by cognitive dysfunction and neuronal loss. 7,8 Some of the effects of positive AMPA receptor modulators are mediated via increased BDNF expression. 9,10 Positive AMPA receptor modulators however are preferred over direct administration of BDNF itself as this class of molecules readily crosses the blood-brain barrier. 11 Brain-derived neurotrophic factor is important for appropriate development and connectivity of neurons as well as their survival. 12,13 In adults, activity dependent modulation of BDNF levels is important for synaptic plasticity and remodeling. 14,15 Activation of the extracellular-regulated kinases (ERKs) pathway by BDNF is important for neuronal survival. 16,17 BDNF mediates activity dependent synaptic plasticity by mechanisms that involve receptor regulation and localized gene transcription. 18,19 At present, it is unclear whether the neuroprotection, synaptic remodeling and plasticity effects of BDNF are related to each other through common downstream elements.Growth-associated protein-43 (GAP-43) is a nervous system specific F-actin regulating phosphoprotein expressed during de...

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Section: Discussionmentioning

confidence: 99%

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

et al. 2009

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“…Moreover, several positive modulators of AMPA-R have shown a distinctive capacity to increase LTP in hippocampus in vivo in rodents, and possess pro-cognitive properties in several behavioral tasks in rodents and primates (Lepagnol et al 1997;Zivkovic et al 1995;Thompson et al 1995;Buccafusco et al 2004;Beracochea et al 2007). One of these compounds-S 18986-has been shown to enhance hippocampal and cortical release of noradrenaline and hippocampal release of acetylcholine (Lockhart et al 2000;Rosi et al 2004). It also displays cognition-enhancing properties in young (Lebrun et al 2000) and aged rodents (Rosi et al 2004;Marighetto et al 2008).…”

Section: Introductionmentioning

confidence: 99%

S 18986 reverses spatial working memory impairments in aged mice: comparison with memantine

et al. 2011

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“…The head of the first family, aniracetam, facilitates the induction of long-term potentiation (Ito et al, 1990;Tang et al, 1991), and the head of the second family, cyclothiazide, potentiates the release of [ 3 H]noradrenaline in rat hippocampal slices (Pittaluga et al, 1999). S18986 is a new pyrrolo-benzothiadiazine derivative (Desos et al, 1996) that activates the release of noradrenaline and acetylcholine in rat hippocampus (Lockhart et al, 2000;Rosi et al, 2004) and enhances rat memory in object-recognition tests (Lebrun et al, 2000).…”

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NEUROPHARMACOKINETICS OF A NEW α-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONIC ACID (AMPA) MODULATOR, S18986 [(S)-2,3-DIHYDRO-[3,4]CYCLOPENTANO-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDE], IN THE RAT

Bourasset¹,

Bernard²,

Muñoz³

et al. 2005

Drug Metab Dispos

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ABSTRACT:The aim of our study was to determine the neuropharmacokinetics of S18986 [(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide], a new positive allosteric modulator of ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type receptors, in the rat. We focused on its blood-brain barrier (BBB) uptake and on its brain intra-and extracellular fluid (bICF-bECF) partitioning. BBB transport of S18986 was measured using the in situ brain perfusion technique. bECF concentrations were determined by microdialysis in the two effector areas, i.e., frontal cortex (FC) and dorsal hippocampus (DH), and blood samples were collected simultaneously through a femoral catheter. Cerebrospinal fluid and brain tissue concentrations were determined using a conventional pharmacokinetic approach. Using all the experimental data, pharmacokinetic modeling was applied to describe the S18986 blood-brain disposition. The brain uptake clearance of S18986 was found to be high, about 20 l s ؊1 g ؊1 . Terminal half-lives were similar in plasma and brain, at around 1 h. Experimental and predicted blood and brain concentrations were a good fit with the pharmacokinetic model, which assumed first-order rate constants at each interface. Ratios of bECF to the unbound plasma area under the curve (AUC) were 0.24 in FC and 0.25 in DH, whereas ratios of bICF/plasma AUC were 1 in FC and 1.5 in DH. We conclude that despite the ratio of bECF/plasma AUC below 1, there is nevertheless an elevated BBB uptake of S18986. This can be explained by the S18986 nonhomogenous bECF/bICF partitioning, since S18986 mainly distributes into hippocampal bICF. This illustrates the importance of taking bECF/ bICF partitioning into account when interpreting the neuropharmacokinetics of a drug.

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(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide: (S18986-1) a positive modulator of AMPA receptors enhances (S)-AMPA-mediated [3H]noradrenaline release from rat hippocampal and frontal cortex slices

Cited by 31 publications

References 34 publications

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986

S 18986 reverses spatial working memory impairments in aged mice: comparison with memantine

NEUROPHARMACOKINETICS OF A NEW α-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONIC ACID (AMPA) MODULATOR, S18986 [(S)-2,3-DIHYDRO-[3,4]CYCLOPENTANO-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDE], IN THE RAT

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